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Moving Myeloid Leukemia Drug Discovery Into the Third Dimension.

ABSTRACT: The development of therapies aimed at leukemia has progressed substantially in the past years but childhood acute myeloid leukemia (AML) remains one of the most challenging cancers to treat. Genomic profiling of AML has greatly enhanced our understanding of the genetic and epigenetic landscape of this high-risk leukemia. With it comes the opportunity to develop targeted therapies that are expected to be more effective and less toxic than current treatment regimens. Nevertheless, often overlooked in leukemia drug discovery are the dynamic interactions between leukemic cells and the bone marrow environment. The interplay between leukemic cells, stromal cells and the extracellular matrix plays critical roles in the development, progression and relapse of AML as well as in drug response and the development of resistance. Here we will review pediatric leukemia with a special focus on acute myeloid disease in children, and discuss the tumor microenvironment in the context of drug resistance and leukemia stem cell survival. We will emphasize how three-dimensional (3D) cell-based drug discovery may offer hope for both the identification and advancement of more effective treatment options for patients suffering from this devastating disease.

SUBMITTER: Cartledge Wolf DM

PROVIDER: S-EPMC6682595 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Moving Myeloid Leukemia Drug Discovery Into the Third Dimension.

Cartledge Wolf Donna M DM Langhans Sigrid A SA

Frontiers in pediatrics 20190730

The development of therapies aimed at leukemia has progressed substantially in the past years but childhood acute myeloid leukemia (AML) remains one of the most challenging cancers to treat. Genomic profiling of AML has greatly enhanced our understanding of the genetic and epigenetic landscape of this high-risk leukemia. With it comes the opportunity to develop targeted therapies that are expected to be more effective and less toxic than current treatment regimens. Nevertheless, often overlooked ...[more]

PMID: 31417884

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Project description:An understanding of parameters that modulate gene transfer in 3-D will assist in the formation of gene delivery systems and scaffolds, which can mediate efficient non-viral delivery for guiding in vivo tissue regeneration and therapy. We have previously demonstrated the cell area and length, integrin expression, and RhoGTPase mediated signalling to be pivotal parameters that guide gene transfer to mouse mesenchymal stem cells (mMSCs) cultured in 2-D and are modulated by ECM proteins. In this study, we were interested in determining if cationic polymer mediated gene transfer to cells seeded in 3-D would occur through different mechanisms as compared to those seeded in 2-D. In particular, we examined the endocytosis pathways used to internalize polyplexes, and the role of cytoskeletal dynamics and RhoGTPases in non-viral gene transfer for cells seeded in 2-D and 3-D. Inhibition of clathrin- and caveolae-mediated endocytosis resulted in a more drastic decrease in overall transgene expression for cells seeded in 3-D than for those in 2-D. In addition, polyplex internalization was only significantly decreased in 3-D when clathrin-mediated endocytosis was inhibited, while caveolae-mediated endocytosis inhibition for cells seeded in 2-D resulted in the strongest polyplex internalization inhibition. Actin and microtubule polymerization affected 2-D and 3-D transfection differently. Microtubule depolymerization enhanced transgene expression in 2-D, but inhibited transgene expression in 3-D. Lastly, inhibition of RhoGTPases also affected 2-D and 3-D transfection differently. The inhibition of ROCK effectors resulted in a decrease of transgene expression and internalization for cells seeded in 3-D, but not in 2-D, and the inhibition of the effector PAK1 resulted in an increase of transgene expression for both 2-D and 3-D. Overall, our study suggests that the process of gene transfer occurs through different mechanisms for cells seeded in 2-D compared to those seeded in 3-D.

Dataset Information

Moving Myeloid Leukemia Drug Discovery Into the Third Dimension.

Publications

Moving Myeloid Leukemia Drug Discovery Into the Third Dimension.

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